Sequential steroid administration of estradiol (E2) and progesterone (P) in spayed pigtailed macaques was used to precisely control the time course of sex skin swelling. After removal of the P implant, the sex skin swelled considerably and the water content of the sex skin increased manyfold over that of back skin. During the swelling phase, hyaluronate biosynthesis in sex skin increased dramatically compared with back skin of the same animals. Collagen synthesis also increased but to a lesser extent. Estrogen receptor levels were undetectable in back skin and very low in spayed animals that had been treated with both E2 and P. After removal of the P implant, both the level of estrogen receptor and the rate of hyaluronate biosynthesis increased. Immunocytochemistry with monoclonal antibodies against the estrogen receptor showed that the dermal fibroblast was the only cell type to stain positively for estrogen receptor. We conclude that the sex skin swelling that follows P withdrawal in pigtailed macaques bearing E2 implants is mediated by estrogen receptors in dermal fibroblasts and is a result of increased hyaluronic acid synthesis by these cells.